Registration Dossier
Registration Dossier
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EC number: 920-008-6 | CAS number: -
Carcinogenicity
Administrative data
Description of key information
The available read across data and weight of evidence demonstrate that Hydrocarbons, C12-C16, n-alkanes, isoalkanes, cyclics, aromatics (2-25%) is highly unlikely to be carcinogenic and is not classifiable as a carcinogen.
Key value for chemical safety assessment
Carcinogenicity: via oral route
Link to relevant study records
- Endpoint:
- carcinogenicity, other
- Remarks:
- Oral, inhalation, and dermal
- Data waiving:
- study scientifically not necessary / other information available
- Justification for data waiving:
- other:
- Endpoint:
- carcinogenicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Basic data given:comparable to guidelines/standards.
- Justification for type of information:
- Hydrocarbons, C12-C16, n-alkanes, isoalkanes, cyclics, aromatics (2-25%) straddles Hydrocarbons, C9-C14, Aliphatics, (2-25% Aromatics) and Hydrocarbons, C14-C20, Aliphatics (2-30% Aromatics). Read across justification documents have been provided for the same in Section 13 of the dossier. For this substance, a worst case scenario approach has been used for each endpoint.
- Reason / purpose for cross-reference:
- read-across: supporting information
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- other: OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
- Principles of method if other than guideline:
- Test type: subchronic
- GLP compliance:
- not specified
- Species:
- rat
- Strain:
- Crj: CD(SD)
- Sex:
- male/female
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- - Concentration in vehicle: constant volume dosage of 5 ml/kg bw
- Duration of treatment / exposure:
- 30 days
- Frequency of treatment:
- daily
- Remarks:
- Doses / Concentrations:
0.14 ml/kg/day (~116 mg/kg bw)
Basis:
other: nominal - Remarks:
- Doses / Concentrations:
0.42 ml/kg/day (~347 mg/kg bw)
Basis:
other: nominal - Remarks:
- Doses / Concentrations:
1.28 ml/kg/day (~1056 mg/kg bw)
Basis:
other: nominal - No. of animals per sex per dose:
- 5 female/5 male
- Control animals:
- yes, concurrent vehicle
- Sacrifice and pathology:
- GROSS PATHOLOGY: Yes, organs examined include kidneys and livers.
HISTOPATHOLOGY: Yes, organs examined include kidneys. - Other examinations:
- Clinical chemistry- including plasma glucose
hematology - including lymphocyte and platelet counts, cell volume, hemoglobin concentration, and erythrocyte counts;
Urinanalysis - including protein concentrations - Clinical signs:
- effects observed, treatment-related
- Mortality:
- mortality observed, treatment-related
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- no effects observed
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Ophthalmological findings:
- not examined
- Haematological findings:
- effects observed, treatment-related
- Clinical biochemistry findings:
- effects observed, treatment-related
- Urinalysis findings:
- effects observed, treatment-related
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Gross pathological findings:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Histopathological findings: neoplastic:
- not examined
- Details on results:
- CLINICAL SIGNS AND MORTALITY
The majority of animals in the 0.42 and 1.48 ml/kg/day groups showed salivation and/or brown facial staining from day 4 onwards, as did three animals in the 0.14 ml/kg/day group. Salivation was normally for a short period, and the staining resolved within 24 hrs.
HAEMATOLOGY
Males rats in the 1.28 ml/kg/day group showed higher lymphocyte and platelet numbers, and slightly lower packed cell volume, hemoglobin concentration and erythrocyte counts.
CLINICAL CHEMISTRY
Plasma glucose levels of rats in the 1.28 ml/kg/day group were lower than controls.
URINALYSIS
Urinary protein concentrations were higher in all male rats in the two higher dose groups, and in 2 males in the lowest dose group.
ORGAN WEIGHTS
Male rats showed a dosage related increase in liver and kidney weights. Female rats only showed higher liver weight at the highest dose level.
GROSS PATHOLOGY
One male rat in the 1.28 ml/kg/day dose group had occasional cystic spaces in the parenchyma of the left kidney.
HISTOPATHOLOGY: NON-NEOPLASTIC
The changes in the kidneys were a slight degeneration of the cells lining the proximal tubules in all treatment groups. There was tubular cell degeneration, tubular dilation with intratubular protein and regeneration. These changes were only found in three males in the low dose groups, and four males each in the medium and high dose groups.
- Dose descriptor:
- LOAEL
- Effect level:
- 0.14 other: ml/kg/day
- Sex:
- male
- Basis for effect level:
- other: This type of renal pathology is specific to male rats due to an alpha2u-globulin-mediated process that is not relevant to humans.
- Dose descriptor:
- NOAEL
- Effect level:
- 0.42 other: ml/kg/day
- Sex:
- female
- Basis for effect level:
- other: 1056 mg/kg bw
- Conclusions:
- The LOAEL for male rats was 0.14 ml/kg/day based on renal damage. This type of renal damage is specific to male rats, and is not relevant to humans. The NOAEL for female rats was 1.28 ml/kg/day.
- Executive summary:
The LOAEL for male rats was 0.14 ml/kg/day based on renal damage. This type of renal damage is specific to male rats, and is not relevant to humans. The NOAEL for female rats was 1.28 ml/kg/day.
This study examined the oral 30 -day subchronic toxicity of BP 8313 to rats. Groups of 5 rats of each sex were given doses of 0.14 (116 mg/kg), 0.42 (347 mg/kg), or 1.28 (1056 mg/kg) mL/kg of test substance in corn oil for 30 days. Animals were examined for clinical signs, mortality, body weight, food consumption, water consumption, and food conversion. After sacrifice clinical chemistry, hematology, clinical chemistry, urinalysis, organ weights, histopathology, and gross pathology were examined. There was no mortality during the experiment. Renal damage was observed in male rats at all dose levels. This type of renal pathology is specific to male rats due to a alpha2u-globulin-mediated process that is not relevant to humans. Female rats exhibited adaptive liver changes at the highest dosage. The LOAEL for male rats was 0.14 ml/kg/day based on renal damage. The female NOAEL was 1.28 (1056 mg/kg) mL/kg.
Referenceopen allclose all
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Quality of whole database:
- Supporting read across studies available for assessment.
Carcinogenicity: via inhalation route
Link to relevant study records
- Endpoint:
- carcinogenicity, other
- Remarks:
- Oral, inhalation, and dermal
- Data waiving:
- study scientifically not necessary / other information available
- Justification for data waiving:
- other:
- Endpoint:
- carcinogenicity: inhalation
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Study period:
- 1980
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Similar or equivalent to OECD TG 413.
- Justification for type of information:
- Hydrocarbons, C12-C16, n-alkanes, isoalkanes, cyclics, aromatics (2-25%) straddles Hydrocarbons, C9-C14, Aliphatics, (2-25% Aromatics) and Hydrocarbons, C14-C20, Aliphatics (2-30% Aromatics). Read across justification documents have been provided for the same in Section 13 of the dossier. For this substance, a worst case scenario approach has been used for each endpoint.
- Reason / purpose for cross-reference:
- read-across: supporting information
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- other: OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day)
- Principles of method if other than guideline:
- Subchronic
- GLP compliance:
- not specified
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Shell Toxicology Laboratory (Tunstall) Breeding Unit
- Age at study initiation: 10-13 weeks
- Weight at study initiation: male mean weight: 396-398, female mean weight: 244-245
- Fasting period before study: food removed during exposure
- Housing: three per sex in hanging aluminum cages with stainless steel mesh bases 14 x 10 x 7 in, with two layers of cages for a total of twelve cages per exposure chamber
- Diet (e.g. ad libitum): LAD 1, Spillers Spratts Ltd., replenished daily after exposure
- Water (e.g. ad libitum): tap water ad libitum
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17-22
- Humidity (%): 32-61
- Route of administration:
- inhalation: vapour
- Type of inhalation exposure (if applicable):
- whole body
- Details on exposure:
- GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 1 m³ aluminum exposure chamber
- Method of holding animals in test chamber: cages
- Source and rate of air: laboratory air
- Method of conditioning air: dust filters
- System of generating particulates/aerosols: Solvent was evaporated into the air stream using micrometering pumps and vaporizers. Vaporizers were quartz tubes heated to a surface temperature required for complete evaporation of the solvent.
- Temperature, humidity, pressure in air chamber: 17-22°C, 32-61%
- Air flow rate: 2.0 ± 0.03 m³/min
- Air change rate:
- Method of particle size determination:
- Treatment of exhaust air: Air was exhausted into the laboratory exhaust which exited on the roof of the laboratory.
TEST ATMOSPHERE
- Brief description of analytical method used: total hydrocarbon analyser fitted with a flame-ionization detector - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Total hydrocarbon analyser fitted with a flame-ionization detector
- Duration of treatment / exposure:
- 6 hours/day
- Frequency of treatment:
- 5 days/week for 13 weeks
- Remarks:
- Doses / Concentrations:
1293 ppm
Basis:
analytical conc. - Remarks:
- Doses / Concentrations:
690 ppm
Basis:
analytical conc. - Remarks:
- Doses / Concentrations:
345 ppm
Basis:
analytical conc. - No. of animals per sex per dose:
- 18 per sex
- Control animals:
- yes, concurrent no treatment
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations: general health and behaviour
BODY WEIGHT: Yes
- Time schedule for examinations: weekly
FOOD CONSUMPTION: Yes
- Time schedule for examinations: weekly
WATER CONSUMPTION: Yes
- Time schedule for examinations: weekly
HAEMATOLOGY: Yes
- Time schedule for collection of blood: end of experiment
- How many animals: all animals
- Parameters checked: erythrocyte count, mean cell volume, hemoglobin, leucocyte count, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, hematocrit, red cell fragilities, reticulocyte count, prothrombin time, kaolin-cephalin coagulation time
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: end of experiment
- How many animals: all animals
- Parameters checked: total protein, urea nitrogen, alkaline phosphatase, aspartate amino transferase, alanine animo transferase, sodium, potassium, chloride, albumin, bilirubin
- Other: Estimations of blood glucose were made after 10 weeks of exposure using samples taken from the tail vein.
- Sacrifice and pathology:
- GROSS PATHOLOGY: Yes, all animals were examined and the following organs weighed: brain, liver, heart, spleen, kidneys, and testes.
HISTOPATHOLOGY: Yes, the following tissues of the high and medium exposure animals and the control animals were examined: mammary gland, mesenteric lymph node, pancreas, stomach, intestine at 5 levels, caecum, spleen, liver, adrenals, kidneys, ovaries or testes, uterus or prostate, seminal vesicles, urinary bladder, thyroid, trachea, heart, lungs, nasal cavity, thymus, eye and lachrymal glands, salivary glands, brain, spinal cord, pituitary, tongue, sciatic nerves, muscle, knee joint and femur, and macroscopic lesions. The kidneys of low exposure males were also examined. - Statistics:
- Body and organ weights were analysed using covariance analysis, with initial body weight as the covariance. Means were adjusted if a significant covariance was found. Organs weights were also analysed using terminal body weights as the covariance. Clinical chemistry and hematological parameters were analysed using analysis of variance. Differences between treatment groups and controls were analysed using Williams t-test. Dunnett's test was used if a monotonic dose response could not be assumed.
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Gross pathological findings:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Histopathological findings: neoplastic:
- no effects observed
- Details on results:
- CLINICAL SIGNS AND MORTALITY
There were no deaths during the experiment. High exposure animals were lethargic when examined 30 minutes after exposure. Animals were fully recovered by the next morning.
BODY WEIGHT AND WEIGHT GAIN
Males in the medium and high exposure groups had body weights significantly lower than controls. High exposure females also had body weights significantly lower than controls.
FOOD CONSUMPTION
No significant differences in food consumption were observed.
WATER CONSUMPTION
Exposed animals showed significant increase in water consumption, particularly animals in the high exposure group.
HAEMATOLOGY
Male PCV, erythrocyte count, mean cell volume, and mean corpuscular hemoglobin were significantly different from controls at all exposure levels. In females, the number of white cells, and mean cell volume were increased in the high exposure group.
CLINICAL CHEMISTRY
Alkaline phosphatase in both sexes, male aspartate amino transferase, and female albumin levels were significantly higher in the high exposure group. Female total protein was also significantly increased in the medium and high exposure groups.
ORGAN WEIGHTS
Male kidney weights at all exposure levels, and spleen weights in the medium and high exposure levels were significantly increased. Female kidney weights at the medium and high exposure levels, and liver weights at all exposure levels were also increased. However, there were no lesions in these organs found during the histopathology examination. These changes in femals were likely hyperfunctional adaptations of the organs rather than a toxic effect.
GROSS PATHOLOGY
Males in the medium and high exposure groups showed a low incidence of splenic enlargement, renal pallor, and hepatic darkening.
HISTOPATHOLOGY: NON-NEOPLASTIC
Kidneys - Male rats in all exposure group showed multiple, hyaline intracytoplasmic, inclusion droplets in the epithelium of the proximal convoluted tubules of their kidneys. This change did not seem to be dose related. These males also showed increase in the number and size of lysosomes in the cytoplasm of the proximal convoluted tubules. Exposure males also had more frequent focal tubular basophilia. Three males in the high exposure group also showed focal tubular dilatation and inspissated debris in the tubular laminae.
Spleen - Males in the medium and high exposure groups showed accelerated erythropoietic activity and increased hemosiderin deposition. Females in the high exposure group showed increased hemosiderin deposition, and mild extramedullary hematopoiesis.
Lungs - No treatment related effects were noted.
- Dose descriptor:
- LOAEC
- Effect level:
- 345 ppm
- Sex:
- male
- Basis for effect level:
- other: increased kidney weights as a result of an alpha2u-globulin-mediated process that is not regarded as relevant to humans
- Dose descriptor:
- NOEC
- Effect level:
- 1 293 ppm
- Sex:
- female
- Basis for effect level:
- other: reduced body weight; no other effects noted
- Dose descriptor:
- NOAEC
- Effect level:
- 690 ppm
- Sex:
- female
- Conclusions:
- The 90-day LOAEC for male rats was 345 ppm (inhalation). This value is based on increased kidney weights as a result of an alpha2u-globulin-mediated process that is not regarded as relevant to humans. The no-observed-effect-concentration (NOEC) was established at 1293 ppm due to a significant body weight reduction. No other effects were noted. The NOAEC for female rats was 690 ppm.
- Executive summary:
This study evaluated the subchronic toxicity of low aromatic white spirits to rats when exposed via inhalation. Groups of 18 rats per sex were exposed to 345, 690, or 1293 ppm of test substance for 6 hrs/day, 5 days/week, for 13 weeks. The highest concentration, 1293 ppm, was near the saturation point for test substance vapor. Rats were observed for clinical signs, mortality, food consumption, water consumption, and body weight. At the end of the exposure period, the animals were sacrificed, and clinical chemistry, hematology, gross pathology, and histopathology parameters were examined. Male rats at all exposure levels had degenerative effects of the as a result of an alpha2u-globulin-mediated process that is not regarded as relevant to humans. The no-observed-effect-concentration (NOEC) was established at 1293 ppm due to a significant body weight reduction. No other effects were noted. The NOAEC for female rats was 690 ppm.
- Endpoint:
- carcinogenicity: inhalation
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Study period:
- 1980
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Similar or equivalent to OECD TG 413.
- Justification for type of information:
- Hydrocarbons, C12-C16, n-alkanes, isoalkanes, cyclics, aromatics (2-25%) straddles Hydrocarbons, C9-C14, Aliphatics, (2-25% Aromatics) and Hydrocarbons, C14-C20, Aliphatics (2-30% Aromatics). Read across justification documents have been provided for the same in Section 13 of the dossier. For this substance, a worst case scenario approach has been used for each endpoint.
- Reason / purpose for cross-reference:
- read-across: supporting information
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- other: OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day)
- Principles of method if other than guideline:
- Subchronic
- GLP compliance:
- not specified
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Shell Toxicology Laboratory (Tunstall) Breeding Unit
- Age at study initiation: 10-13 weeks
- Weight at study initiation: male mean weight: 396-398, female mean weight: 244-245
- Fasting period before study: food removed during exposure
- Housing: three per sex in hanging aluminum cages with stainless steel mesh bases 14 x 10 x 7 in, with two layers of cages for a total of twelve cages per exposure chamber
- Diet (e.g. ad libitum): LAD 1, Spillers Spratts Ltd., replenished daily after exposure
- Water (e.g. ad libitum): tap water ad libitum
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17-22
- Humidity (%): 32-61
- Route of administration:
- inhalation: vapour
- Type of inhalation exposure (if applicable):
- whole body
- Details on exposure:
- GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 1 m³ aluminum exposure chamber
- Method of holding animals in test chamber: cages
- Source and rate of air: laboratory air
- Method of conditioning air: dust filters
- System of generating particulates/aerosols: Solvent was evaporated into the air stream using micrometering pumps and vaporizers. Vaporizers were quartz tubes heated to a surface temperature required for complete evaporation of the solvent.
- Temperature, humidity, pressure in air chamber: 17-22°C, 32-61%
- Air flow rate: 2.0 ± 0.03 m³/min
- Air change rate:
- Method of particle size determination:
- Treatment of exhaust air: Air was exhausted into the laboratory exhaust which exited on the roof of the laboratory.
TEST ATMOSPHERE
- Brief description of analytical method used: total hydrocarbon analyser fitted with a flame-ionization detector - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Total hydrocarbon analyser fitted with a flame-ionization detector
- Duration of treatment / exposure:
- 6 hours/day
- Frequency of treatment:
- 5 days/week for 13 weeks
- Remarks:
- Doses / Concentrations:
1293 ppm
Basis:
analytical conc. - Remarks:
- Doses / Concentrations:
690 ppm
Basis:
analytical conc. - Remarks:
- Doses / Concentrations:
345 ppm
Basis:
analytical conc. - No. of animals per sex per dose:
- 18 per sex
- Control animals:
- yes, concurrent no treatment
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations: general health and behaviour
BODY WEIGHT: Yes
- Time schedule for examinations: weekly
FOOD CONSUMPTION: Yes
- Time schedule for examinations: weekly
WATER CONSUMPTION: Yes
- Time schedule for examinations: weekly
HAEMATOLOGY: Yes
- Time schedule for collection of blood: end of experiment
- How many animals: all animals
- Parameters checked: erythrocyte count, mean cell volume, hemoglobin, leucocyte count, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, hematocrit, red cell fragilities, reticulocyte count, prothrombin time, kaolin-cephalin coagulation time
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: end of experiment
- How many animals: all animals
- Parameters checked: total protein, urea nitrogen, alkaline phosphatase, aspartate amino transferase, alanine animo transferase, sodium, potassium, chloride, albumin, bilirubin
- Other: Estimations of blood glucose were made after 10 weeks of exposure using samples taken from the tail vein.
- Sacrifice and pathology:
- GROSS PATHOLOGY: Yes, all animals were examined and the following organs weighed: brain, liver, heart, spleen, kidneys, and testes.
HISTOPATHOLOGY: Yes, the following tissues of the high and medium exposure animals and the control animals were examined: mammary gland, mesenteric lymph node, pancreas, stomach, intestine at 5 levels, caecum, spleen, liver, adrenals, kidneys, ovaries or testes, uterus or prostate, seminal vesicles, urinary bladder, thyroid, trachea, heart, lungs, nasal cavity, thymus, eye and lachrymal glands, salivary glands, brain, spinal cord, pituitary, tongue, sciatic nerves, muscle, knee joint and femur, and macroscopic lesions. The kidneys of low exposure males were also examined. - Statistics:
- Body and organ weights were analysed using covariance analysis, with initial body weight as the covariance. Means were adjusted if a significant covariance was found. Organs weights were also analysed using terminal body weights as the covariance. Clinical chemistry and hematological parameters were analysed using analysis of variance. Differences between treatment groups and controls were analysed using Williams t-test. Dunnett's test was used if a monotonic dose response could not be assumed.
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Gross pathological findings:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Histopathological findings: neoplastic:
- no effects observed
- Details on results:
- CLINICAL SIGNS AND MORTALITY
There were no deaths during the experiment. High exposure animals were lethargic when examined 30 minutes after exposure. Animals were fully recovered by the next morning.
BODY WEIGHT AND WEIGHT GAIN
Males in the medium and high exposure groups had body weights significantly lower than controls. High exposure females also had body weights significantly lower than controls.
FOOD CONSUMPTION
No significant differences in food consumption were observed.
WATER CONSUMPTION
Exposed animals showed significant increase in water consumption, particularly animals in the high exposure group.
HAEMATOLOGY
Male PCV, erythrocyte count, mean cell volume, and mean corpuscular hemoglobin were significantly different from controls at all exposure levels. In females, the number of white cells, and mean cell volume were increased in the high exposure group.
CLINICAL CHEMISTRY
Alkaline phosphatase in both sexes, male aspartate amino transferase, and female albumin levels were significantly higher in the high exposure group. Female total protein was also significantly increased in the medium and high exposure groups.
ORGAN WEIGHTS
Male kidney weights at all exposure levels, and spleen weights in the medium and high exposure levels were significantly increased. Female kidney weights at the medium and high exposure levels, and liver weights at all exposure levels were also increased. However, there were no lesions in these organs found during the histopathology examination. These changes in femals were likely hyperfunctional adaptations of the organs rather than a toxic effect.
GROSS PATHOLOGY
Males in the medium and high exposure groups showed a low incidence of splenic enlargement, renal pallor, and hepatic darkening.
HISTOPATHOLOGY: NON-NEOPLASTIC
Kidneys - Male rats in all exposure group showed multiple, hyaline intracytoplasmic, inclusion droplets in the epithelium of the proximal convoluted tubules of their kidneys. This change did not seem to be dose related. These males also showed increase in the number and size of lysosomes in the cytoplasm of the proximal convoluted tubules. Exposure males also had more frequent focal tubular basophilia. Three males in the high exposure group also showed focal tubular dilatation and inspissated debris in the tubular laminae.
Spleen - Males in the medium and high exposure groups showed accelerated erythropoietic activity and increased hemosiderin deposition. Females in the high exposure group showed increased hemosiderin deposition, and mild extramedullary hematopoiesis.
Lungs - No treatment related effects were noted.
- Dose descriptor:
- LOAEC
- Effect level:
- 345 ppm
- Sex:
- male
- Basis for effect level:
- other: increased kidney weights as a result of an alpha2u-globulin-mediated process that is not regarded as relevant to humans
- Dose descriptor:
- NOEC
- Effect level:
- 1 293 ppm
- Sex:
- female
- Basis for effect level:
- other: reduced body weight; no other effects noted
- Dose descriptor:
- NOAEC
- Effect level:
- 690 ppm
- Sex:
- female
- Conclusions:
- The 90-day LOAEC for male rats was 345 ppm (inhalation). This value is based on increased kidney weights as a result of an alpha2u-globulin-mediated process that is not regarded as relevant to humans. The no-observed-effect-concentration (NOEC) was established at 1293 ppm due to a significant body weight reduction. No other effects were noted. The NOAEC for female rats was 690 ppm.
- Executive summary:
This study evaluated the subchronic toxicity of low aromatic white spirits to rats when exposed via inhalation. Groups of 18 rats per sex were exposed to 345, 690, or 1293 ppm of test substance for 6 hrs/day, 5 days/week, for 13 weeks. The highest concentration, 1293 ppm, was near the saturation point for test substance vapor. Rats were observed for clinical signs, mortality, food consumption, water consumption, and body weight. At the end of the exposure period, the animals were sacrificed, and clinical chemistry, hematology, gross pathology, and histopathology parameters were examined. Male rats at all exposure levels had degenerative effects of the as a result of an alpha2u-globulin-mediated process that is not regarded as relevant to humans. The no-observed-effect-concentration (NOEC) was established at 1293 ppm due to a significant body weight reduction. No other effects were noted. The NOAEC for female rats was 690 ppm.
- Endpoint:
- carcinogenicity: inhalation
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Study period:
- 1980
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Similar or equivalent to OECD TG 413.
- Justification for type of information:
- Hydrocarbons, C12-C16, n-alkanes, isoalkanes, cyclics, aromatics (2-25%) straddles Hydrocarbons, C9-C14, Aliphatics, (2-25% Aromatics) and Hydrocarbons, C14-C20, Aliphatics (2-30% Aromatics). Read across justification documents have been provided for the same in Section 13 of the dossier. For this substance, a worst case scenario approach has been used for each endpoint.
- Reason / purpose for cross-reference:
- read-across: supporting information
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- other: OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day)
- Principles of method if other than guideline:
- Subchronic
- GLP compliance:
- not specified
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Shell Toxicology Laboratory (Tunstall) Breeding Unit
- Age at study initiation: 10-13 weeks
- Weight at study initiation: male mean weight: 396-398, female mean weight: 244-245
- Fasting period before study: food removed during exposure
- Housing: three per sex in hanging aluminum cages with stainless steel mesh bases 14 x 10 x 7 in, with two layers of cages for a total of twelve cages per exposure chamber
- Diet (e.g. ad libitum): LAD 1, Spillers Spratts Ltd., replenished daily after exposure
- Water (e.g. ad libitum): tap water ad libitum
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17-22
- Humidity (%): 32-61
- Route of administration:
- inhalation: vapour
- Type of inhalation exposure (if applicable):
- whole body
- Details on exposure:
- GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 1 m³ aluminum exposure chamber
- Method of holding animals in test chamber: cages
- Source and rate of air: laboratory air
- Method of conditioning air: dust filters
- System of generating particulates/aerosols: Solvent was evaporated into the air stream using micrometering pumps and vaporizers. Vaporizers were quartz tubes heated to a surface temperature required for complete evaporation of the solvent.
- Temperature, humidity, pressure in air chamber: 17-22°C, 32-61%
- Air flow rate: 2.0 ± 0.03 m³/min
- Air change rate:
- Method of particle size determination:
- Treatment of exhaust air: Air was exhausted into the laboratory exhaust which exited on the roof of the laboratory.
TEST ATMOSPHERE
- Brief description of analytical method used: total hydrocarbon analyser fitted with a flame-ionization detector - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Total hydrocarbon analyser fitted with a flame-ionization detector
- Duration of treatment / exposure:
- 6 hours/day
- Frequency of treatment:
- 5 days/week for 13 weeks
- Remarks:
- Doses / Concentrations:
1293 ppm
Basis:
analytical conc. - Remarks:
- Doses / Concentrations:
690 ppm
Basis:
analytical conc. - Remarks:
- Doses / Concentrations:
345 ppm
Basis:
analytical conc. - No. of animals per sex per dose:
- 18 per sex
- Control animals:
- yes, concurrent no treatment
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations: general health and behaviour
BODY WEIGHT: Yes
- Time schedule for examinations: weekly
FOOD CONSUMPTION: Yes
- Time schedule for examinations: weekly
WATER CONSUMPTION: Yes
- Time schedule for examinations: weekly
HAEMATOLOGY: Yes
- Time schedule for collection of blood: end of experiment
- How many animals: all animals
- Parameters checked: erythrocyte count, mean cell volume, hemoglobin, leucocyte count, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, hematocrit, red cell fragilities, reticulocyte count, prothrombin time, kaolin-cephalin coagulation time
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: end of experiment
- How many animals: all animals
- Parameters checked: total protein, urea nitrogen, alkaline phosphatase, aspartate amino transferase, alanine animo transferase, sodium, potassium, chloride, albumin, bilirubin
- Other: Estimations of blood glucose were made after 10 weeks of exposure using samples taken from the tail vein.
- Sacrifice and pathology:
- GROSS PATHOLOGY: Yes, all animals were examined and the following organs weighed: brain, liver, heart, spleen, kidneys, and testes.
HISTOPATHOLOGY: Yes, the following tissues of the high and medium exposure animals and the control animals were examined: mammary gland, mesenteric lymph node, pancreas, stomach, intestine at 5 levels, caecum, spleen, liver, adrenals, kidneys, ovaries or testes, uterus or prostate, seminal vesicles, urinary bladder, thyroid, trachea, heart, lungs, nasal cavity, thymus, eye and lachrymal glands, salivary glands, brain, spinal cord, pituitary, tongue, sciatic nerves, muscle, knee joint and femur, and macroscopic lesions. The kidneys of low exposure males were also examined. - Statistics:
- Body and organ weights were analysed using covariance analysis, with initial body weight as the covariance. Means were adjusted if a significant covariance was found. Organs weights were also analysed using terminal body weights as the covariance. Clinical chemistry and hematological parameters were analysed using analysis of variance. Differences between treatment groups and controls were analysed using Williams t-test. Dunnett's test was used if a monotonic dose response could not be assumed.
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Gross pathological findings:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Histopathological findings: neoplastic:
- no effects observed
- Details on results:
- CLINICAL SIGNS AND MORTALITY
There were no deaths during the experiment. High exposure animals were lethargic when examined 30 minutes after exposure. Animals were fully recovered by the next morning.
BODY WEIGHT AND WEIGHT GAIN
Males in the medium and high exposure groups had body weights significantly lower than controls. High exposure females also had body weights significantly lower than controls.
FOOD CONSUMPTION
No significant differences in food consumption were observed.
WATER CONSUMPTION
Exposed animals showed significant increase in water consumption, particularly animals in the high exposure group.
HAEMATOLOGY
Male PCV, erythrocyte count, mean cell volume, and mean corpuscular hemoglobin were significantly different from controls at all exposure levels. In females, the number of white cells, and mean cell volume were increased in the high exposure group.
CLINICAL CHEMISTRY
Alkaline phosphatase in both sexes, male aspartate amino transferase, and female albumin levels were significantly higher in the high exposure group. Female total protein was also significantly increased in the medium and high exposure groups.
ORGAN WEIGHTS
Male kidney weights at all exposure levels, and spleen weights in the medium and high exposure levels were significantly increased. Female kidney weights at the medium and high exposure levels, and liver weights at all exposure levels were also increased. However, there were no lesions in these organs found during the histopathology examination. These changes in femals were likely hyperfunctional adaptations of the organs rather than a toxic effect.
GROSS PATHOLOGY
Males in the medium and high exposure groups showed a low incidence of splenic enlargement, renal pallor, and hepatic darkening.
HISTOPATHOLOGY: NON-NEOPLASTIC
Kidneys - Male rats in all exposure group showed multiple, hyaline intracytoplasmic, inclusion droplets in the epithelium of the proximal convoluted tubules of their kidneys. This change did not seem to be dose related. These males also showed increase in the number and size of lysosomes in the cytoplasm of the proximal convoluted tubules. Exposure males also had more frequent focal tubular basophilia. Three males in the high exposure group also showed focal tubular dilatation and inspissated debris in the tubular laminae.
Spleen - Males in the medium and high exposure groups showed accelerated erythropoietic activity and increased hemosiderin deposition. Females in the high exposure group showed increased hemosiderin deposition, and mild extramedullary hematopoiesis.
Lungs - No treatment related effects were noted.
- Dose descriptor:
- LOAEC
- Effect level:
- 345 ppm
- Sex:
- male
- Basis for effect level:
- other: increased kidney weights as a result of an alpha2u-globulin-mediated process that is not regarded as relevant to humans
- Dose descriptor:
- NOEC
- Effect level:
- 1 293 ppm
- Sex:
- female
- Basis for effect level:
- other: reduced body weight; no other effects noted
- Dose descriptor:
- NOAEC
- Effect level:
- 690 ppm
- Sex:
- female
- Conclusions:
- The 90-day LOAEC for male rats was 345 ppm (inhalation). This value is based on increased kidney weights as a result of an alpha2u-globulin-mediated process that is not regarded as relevant to humans. The no-observed-effect-concentration (NOEC) was established at 1293 ppm due to a significant body weight reduction. No other effects were noted. The NOAEC for female rats was 690 ppm.
- Executive summary:
This study evaluated the subchronic toxicity of low aromatic white spirits to rats when exposed via inhalation. Groups of 18 rats per sex were exposed to 345, 690, or 1293 ppm of test substance for 6 hrs/day, 5 days/week, for 13 weeks. The highest concentration, 1293 ppm, was near the saturation point for test substance vapor. Rats were observed for clinical signs, mortality, food consumption, water consumption, and body weight. At the end of the exposure period, the animals were sacrificed, and clinical chemistry, hematology, gross pathology, and histopathology parameters were examined. Male rats at all exposure levels had degenerative effects of the as a result of an alpha2u-globulin-mediated process that is not regarded as relevant to humans. The no-observed-effect-concentration (NOEC) was established at 1293 ppm due to a significant body weight reduction. No other effects were noted. The NOAEC for female rats was 690 ppm.
- Endpoint:
- carcinogenicity: inhalation
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Study period:
- 1979
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Comparable to guideline study.
- Justification for type of information:
- Hydrocarbons, C12-C16, n-alkanes, isoalkanes, cyclics, aromatics (2-25%) straddles Hydrocarbons, C9-C14, Aliphatics, (2-25% Aromatics) and Hydrocarbons, C14-C20, Aliphatics (2-30% Aromatics). Read across justification documents have been provided for the same in Section 13 of the dossier. For this substance, a worst case scenario approach has been used for each endpoint.
- Reason / purpose for cross-reference:
- read-across: supporting information
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- other: OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day)
- Principles of method if other than guideline:
- subchronic
- GLP compliance:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Breeding Laboratories
- Age at study initiation: 4 weeks males, 5 weeks females
- Weight at study initiation: males 142-214 g, females 140-189 g
- Housing: elevated stainless steel wire mesh cages, individually outside of chamber, pairs within exposure chamber
- Diet (e.g. ad libitum): Purina Laboratory Chow, ad libitum except during exposure
- Water (e.g. ad libitum): ad libitum except during exposure
- Acclimation period:
IN-LIFE DATES: From: April 17, 1978 To: July 12, 1978 - Route of administration:
- inhalation: vapour
- Type of inhalation exposure (if applicable):
- whole body
- Details on exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: stainless steel and glass chamber, 760 l
- Method of conditioning air: Test substance was metered using a syringe pump driven 50 cc Tomac glass syringe from a 500 ml Erlenmeyer flask into a heated flask and flash evaporated. Clean air was passed through this flask to pick up vapor. The test atmosphere was then fed into the chamber air inlet line where it was diluted to the desired concentration.
- Temperature, humidity, pressure in air chamber:
- Air flow rate: 134 lpm
- Air change rate: 7.46 min, with a 99% equilibration time of 34.3 min.
TEST ATMOSPHERE
- Brief description of analytical method used: Miran IA Ambient Air Analyser IR analyzed at 3.4 microns. Samples were drawn at 1, 3, and 5 hrs of exposure. Charcoal trapped vapor samples were also analyzed using GC.
- Samples taken from breathing zone: yes
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Miran IA Ambient Air Analyser IR analyzed at 3.4 microns. Samples were drawn at 1, 3, and 5 hrs of exposure. Charcoal trapped vapor samples were also analyzed using GC.
- Duration of treatment / exposure:
- 6 hrs/day
- Frequency of treatment:
- 5 days/week for 12 weeks
- Remarks:
- Doses / Concentrations:
100 ppm
Basis:
nominal conc. - Remarks:
- Doses / Concentrations:
300 ppm
Basis:
nominal conc. - Remarks:
- Doses / Concentrations:
103 ppm
Basis:
analytical conc. - Remarks:
- Doses / Concentrations:
294 ppm
Basis:
analytical conc. - No. of animals per sex per dose:
- 35 per sex/per dose
- Control animals:
- yes, concurrent no treatment
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Weekly
BODY WEIGHT: Yes
- Time schedule for examinations: weekly starting five days prior to exposure
HAEMATOLOGY: Yes
- Time schedule for collection of blood: day 0, 4 weeks, 8 weeks, and 12 weeks
- How many animals: 10 animals per sex
- Parameters examined: hemoglobin, hematocrit, erythrocyte count, clotting time, total and differential leucocytes
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: day 0, 4 weeks, 8 weeks, and 12 weeks
- How many animals: 10 animals per sex
- Parameters examined: blood urea nitrogen, serum glutamic pyruvic transaminase, alkaline phosphatase
- Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
10 animals per sex per group were sacrificed at 4, 8, and 12 weeks (all survivors) by exsanguination with anesthesia. The adrenals, brain, gonads, kidneys, liver, and lungs were weighed.
HISTOPATHOLOGY: Yes
The organs of the sacrificed animals from groups I and III were examined histopathologically. The following organs were examined: adrenals, bone marrow, brain, eye, gonad, heart, colon, duodenum, ileum, kidneys, liver, lung, lymph node, mammary gland, pancreas, pituitary, salivary gland, skeletal muscle, skin, spinal cord, spleen, stomach, thyroid, trachea, urinary bladder, uterus or prostate, gross lesions, tissue masses.
- Statistics:
- hematology, and clinical chemistry: Snedecor, GS, and Cochran, WG, Statistical Methods. 6th ed., Iowa State University Press, Ames, 1967, 104-106, 114-119.
body weight, organ weight, and organ/body weight ratios: Dunnett, CW, J. Am. Stat. Assn. 50: 1096-1121, 1955, and Biometrics 20: 482, September, 1964. - Clinical signs:
- effects observed, treatment-related
- Mortality:
- mortality observed, treatment-related
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- no effects observed
- Details on results:
- CLINICAL SIGNS AND MORTALITY
There was no mortality during the study. Females in both exposure groups had yellow staining of the ano-genital fur, which was possibly treatment related. Several animals in all groups exhibited dry rales, mucoid nasal discharge, and red nasal discharge. There was not a clear treatment related pattern. A few animals in all groups exhibited moist rales, chromodacryorrhea, excessive lacrimation, excessive salivation, alopecia, and brown staining of the ano-genital area. There was singular observations of a film covered eye and labored breathing in the high exposure group, and also one observation of loose stool in this group.
BODY WEIGHT AND WEIGHT GAIN
Male body weights were significantly increased at week 2 in both exposure groups. Females in the 300 ppm exposure group had significantly decreased body weights at day 0, week 1, and week 3. These weight differences were not considered to be treatment related.
HAEMATOLOGY
A significant decrease in hematocrit levels was seen in males exposed to 300 ppm at week 8 and week 12. Females in the 100 ppm group had decreased hematocrit values at week 4, and week 8, and females in the 300 ppm group had decreased values at week 4 only. Hemoglobin values were decreased in 100 ppm and 300 ppm exposed females at week 4, and 300 ppm exposed females had significantly decreased mean red blood cell counts at week 4. None of these findings appeared to be biologically significant. Males in the 300 ppm exposure group had elevated mean total leucocyte values at week 12. This was possibly treatment related.
CLINICAL CHEMISTRY
A significant increase in blood urea was seen in both groups of exposed males, indicating a possible treatment related effect. The males in the 100 ppm group had decreased mean glucose level at week 12. Females in the 300 ppm exposure group had decreased mean serum glutamic pyruvic transaminase level in week 4. These effects did not show a treatment related pattern, or indicate an abnormal condition, so they were not considered significant.
ORGAN WEIGHTS
Male kidney weight and kidney/body weight ratios were significantly elevated in the 100 ppm group at the week 4 sacrifice. At the week 12 sacrifice, males in both exposure groups had significantly elevated kidney/body weight ratios, and males in the 300 ppm group also had significanlty elevated kidney weights. At the week 8 sacrifice, females in the 300 ppm exposure group also had elevated kidney weights, and kidney/body weight ratios. These effects did not follow a clear dose related pattern.
HISTOPATHOLOGY
No treatment related effects were observed. - Dose descriptor:
- LOAEC
- Effect level:
- 100 ppm
- Sex:
- male
- Basis for effect level:
- other: increased kidney weights as a result of an alpha2u-globulin-mediated process that is not regarded as relevant to humans
- Dose descriptor:
- NOAEL
- Effect level:
- >= 300 ppm
- Sex:
- female
- Conclusions:
- For male rats, the LOAEC was 100 ppm via inhalation. This value is based on kidney effects due to a alpha2u-globulin-mediated process that is not regarded as relevant to humans that are not relevant to humans. For female rats, the NOAEC was 300 ppm. These results do not warrant classification under either the Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC or under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP).
- Executive summary:
This study examined the subchronic toxicity of MRD-78-25 to rats via inhalation. Groups of 35 rats per sex were exposed to 0, 100, or 300 ppm of test substance vapors. Exposure was 6 hrs/day, 5 days/week, for 12 weeks. 10 rats/sex from each group were sacrificed at week 4 and week 8. Animals were observed for clinical signs daily, and weighed weekly. At the end of the study, all surviving animals were sacrificed. After sacrifice, hematological, clinical chemistry, and histopathological parameters were examined. There was no treatment related mortality during the study, and no treatment related body weight effects. For male rats, the LOAEC was 100 ppm via inhalation. This value is based on kidney effects due to a alpha2u-globulin-mediated process that is not regarded as relevant to humans that are not relevant to humans. For female rats, the NOAEC was 300 ppm. These results do not warrant classification under either the Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC or under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP).
Referenceopen allclose all
Mean Body Weights of Male Rats (g)
Mean Body Weights of Female Rats (g)
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Mean Body Weights of Male Rats (g)
Mean Body Weights of Female Rats (g)
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Mean Body Weights of Male Rats (g)
Mean Body Weights of Female Rats (g)
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Mean Body Weight of Male Rats
Mean Body Weight of Female Rats
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Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Quality of whole database:
- Supporting read across studies available for assessment.
Carcinogenicity: via dermal route
Link to relevant study records
- Endpoint:
- carcinogenicity: dermal
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Study period:
- 1987
- Reliability:
- 4 (not assignable)
- Rationale for reliability incl. deficiencies:
- other: Acceptable well-documented study report which meets basic scientific principles.
- Justification for type of information:
- The justification for read across is provided as an attachment in IUCLID Section 13.Hydrocarbons, C12-C16, n-alkanes, isoalkanes, cyclics, aromatics (2-25%) straddles Hydrocarbons, C9-C14, Aliphatics, (2-25% Aromatics) and Hydrocarbons, C14-C20, Aliphatics (2-30% Aromatics). Read across justification documents have been provided for the same in Section 13 of the dossier. For this substance, a worst case scenario approach has been used for each endpoint.
- Reason / purpose for cross-reference:
- read-across: supporting information
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- Drilling Fluid BP83HF was examined in the Rapid Cancer Screening Test in order to predict its likely potential to cause skin cancer. See References
(1) Ingram, A.J., and Grasso, P., Nuclear enlargement and DNA synthesis in mouse epidermis treated with carcinogen and promoter. Exp. Pathol. (1977), 14, 233-242.
(2) Ingram, A.J., Interaction of Benzo(a)pyrene and an hyperplastic agent in epidermal nuclear enlargement
in the mouse; A dose-response study. Chem-Biol. interactions (1979), 26, 102-113.
(3) Ingram, A.J., and Grasso, P., Nuclear enlargment in mouse skin as a possible indicator of skin carcinogenicity. Human Toxicology (1983), 2:560-561.
(4) Ingram, A.J., and Grasso, P., Nuclear enlargement, an early change produced in mouse epidermis by
carcinogenic chemicals applied topically in the presence of a promoter. J. Appl. Tox(1985) 5_, 53-60.
(5) Ingram, A.J., and Grasso P. Nuclear enlargement produced in mouse skin by carcinogenic mineral oils. J. Appl. Tox. - GLP compliance:
- yes
- Species:
- mouse
- Strain:
- other: TO strain
- Sex:
- female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Olac Ltd.
- Sex: Females (45)
- Housing: groups of five
- Diet (e.g. ad libitum): Labsure Lab Animal Diet No. 1
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 10d - Route of administration:
- dermal
- Vehicle:
- other: 0.2% croton oil in methyl ethyl ketone
- Details on exposure:
- 0.1 ml of the appropriate test solution was applied to the clipped back of each mouse at approximately 11.00 hours and 16.00 hours on Day 0 and at approximately 09.00 hours and 16.00 hours on Days 1 and 2. On day 3 the mice were killed, and the back skin was fixed in phosphate buffered formalin.
- Analytical verification of doses or concentrations:
- no
- Duration of treatment / exposure:
- 3 days
- Frequency of treatment:
- 0.1 ml of the appropriate test solution was applied to the clipped back of each mouse at approximately 11.00 hours and 16.00 hours on Day 0 and at approximately 09.00 hours and 16.00 hours on Days 1 and 2. On day 3 the mice were killed, and the back skin was fixed in phosphate buffered formalin.
- Post exposure period:
- On day 3 the mice were killed, and the back skin was fixed in phosphate buffered formalin.
- Remarks:
- Doses / Concentrations:
0.1mL
Basis:
nominal conc. - No. of animals per sex per dose:
- 5 females per treatment group
5 females - BP83HF
5 females - Positive Control: Carcinogenic Oil, OHC No. 682
5 females - Technical White Oil Nil, OHC No. 681 - Control animals:
- yes, concurrent vehicle
- Details on study design:
- 0.1 ml of the appropriate test solution was applied to the clipped back of each mouse at approximately 11.00 hours and 16.00 hours on Day 0 and at approximately 09.00 hours and 16.00 hours on Days 1 and 2. On day 3 the mice were killed, and the back skin was fixed in phosphate buffered formalin.
- Positive control:
- Positive Control: Carcinogenic Oil, OHC No. 682
- Sacrifice and pathology:
- Histology
After being left to fix for a minimum of 10 days, a narrow longitudinal strip of skin was cut from the middle of the treatment area of the skin of each mouse, processed and paraffin-wax embedded. A single longitudinal skin section (1-2 um) was cut from each and, after removal of the RNA with 1% KOH in 70% alcohol the sections were stained by the Gallocyanin-chromalum method for nucleic acids.
Hyperplasia and Necrosis
Before Quantimet evaluation the slides were checked microscopically to ensure that evidence of epidermal hyperplasia was present and to assess the degree of any necrosis present.
Quantimet Evaluation
The slides were selected at random and the histology reference numbers were covered during the quantimet reading so that the slides were read without reference to treatment. For each slide the area of skin showing maximum nuclear size was identified and marked with a black felt-tip pen. 100 epidermal nuclei in the identified region of each slide were measured by means of the Quantimet 720D image analyser linked to a Hewlett-Packard HP 9830 such that individual and mean nuclear areas were printed out, together with a size distribution at size intervals of 5 µm2. - Statistics:
- Data Analysis
When the slides were identified and grouped, the group mean nuclear areas were calculated. The 10 mice in Groups 1 and 2 were considered to form a single negative control group for the purposes of comparison between groups. By subtracting the mean nuclear area for the negative control group from that of each of the other groups the mean nuclear enlargements were calculated. Mean nuclear areas were compared statistically using the Wilcoxon's Sum of Ranks Test to assess the significance of any difference between the control and test groups. In addition, the nuclear area of the 99th percentile of the negative control group was deduced. The frequency of nuclei larger than this was then determined for each group and expressed as a ratio of the negative control group frequency, making due allowance for animal numbers.
Frequency ratio = (Frequency greater than control 99th percentile) / (1x Number of animals in group)
The frequency of nuclei larger than the 99th percentile was determined from the size range distributions. Where the 99th percentile falls within a size range, a proportion of the test group frequency within this range is used. The proportion is based on the proportion of nuclei within the control group required to make up to the 99th percentile. If, for instance 4 nuclei within the 65-70 µm2 size range are required to make up the 99th percentile and 6 nuclei lie in this range then the 99th percentile is 65 + (4/6 x 5) = 65 + 10/3 = 68.33 µm2. Two nuclei are beyond the 99th percentile in the control groups therefore for each test group 2/6 of the nuclei lying in the 65-70 µm2 size range plus any larger than 70µm2 are regarded as being beyond the 99th percentile.
Positive results are indicated if nuclear enlargement is statistically significant (P<0.05) and the frequency ratio is 3.0 or higher. If there is no statistically significant nuclear enlargement and the frequency ratio is less than 3.0 the results are negative. - Clinical signs:
- not examined
- Mortality:
- not examined
- Body weight and weight changes:
- not examined
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- no effects observed
- Details on results:
- Epidermal Hyperplasia and Other Skin Changes
Epidermal hyperplasia in the BP83HF and control groups was sufficient for a valid test. Epidermal necrosis was mainly limited to foci in the negative control groups, whereas 2/5 animals in the group treated with BP83HF showed more widespread necrosis. In the positive control group more widespread necrosis was evident in all animals and in 2 out of 5 animals this prevented measurement of nuclear size; however in the other animals of this group and in all animals of other groups, sufficient intact epidermis remained.
Nuclear Enlargement and Frequency Ratio
The nuclear enlargement for the positive control oil produced clear evidence of significant mean nuclear enlargement (45.2 +/- 1.3) and a frequency ratio of 6.5, indicating the test was valid. The negative control showed no effects; nuclear enlargement (39.4 +/- 0.8). BP83HF gave a clear negative result with respect to both parameters; nuclear enlargement (40.1 +/- 1.0) and a frequency ratio of 1.2. - Conclusions:
- The negative result obtained with BP83HF indicates that this oil would be unlikely to produce skin tumors in long-term mouse skin-painting studies and would be unlikely to present a carcinogenic hazard to man under conditions of repeated skin contact.
- Executive summary:
BP83HF was examined in the Rapid Cancer Screening Test in order to predict its likely potential to cause skin cancer. Mice were exposed to either BP83HF, a positive or negative control. 0.1 ml of the appropriate test solution was applied to the clipped back of each mouse at approximately 11.00 hours and 16.00 hours on Day 0 and at approximately 09.00 hours and 16.00 hours on Days 1 and 2. On day 3 the mice were killed, and the back skin was fixed in phosphate buffered formalin. A histological examination was performed on skin cut from the middle of the treatment area of the skin of each mouse. Slides were selected at random for the quantimet reading and the area of skin showing maximum nuclear size was identified and data was tabulated. Individual, mean nuclear areas, and size distribution of nuclear size was examined to determine evidence of epidermal hyperplasia and necrosis. The negative result obtained with BP83HF indicates that this oil would be unlikely to produce skin tumors in long-term mouse skin-painting studies and would be unlikely to present a carcinogenic hazard to man under conditions of repeated skin contact.
- Endpoint:
- carcinogenicity: dermal
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Study period:
- 1985/07/11 - 1985/07/31
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Acceptable well-documented study report which meets basic scientific principles: GLP.
- Justification for type of information:
- Hydrocarbons, C12-C16, n-alkanes, isoalkanes, cyclics, aromatics (2-25%) straddles Hydrocarbons, C9-C14, Aliphatics, (2-25% Aromatics) and Hydrocarbons, C14-C20, Aliphatics (2-30% Aromatics). Read across justification documents have been provided for the same in Section 13 of the dossier. For this substance, a worst case scenario approach has been used for each endpoint.
- Reason / purpose for cross-reference:
- read-across: supporting information
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- other: OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
- Deviations:
- yes
- Remarks:
- yes occlusive dressing used; 24 hour exposure
- Principles of method if other than guideline:
- Type of method: in vivo
- GLP compliance:
- yes
- Species:
- rabbit
- Strain:
- New Zealand White
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles Rivers UK Ltd
-Sex: Male (10); Female (10)
- Age at study initiation: 6 weeks
- Weight at study initiation: Male: 125-135g; Female: 110-115g
- Housing: individually housed
- Diet (e.g. ad libitum): No. 1, expanded pelleted maintenance diet for rats and mice from Special Diet Services Ltd., ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 6-day acclimatisation
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22-25
- Humidity (%): 58-90
- Photoperiod (hrs dark / hrs light): 12/12 - Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- Type of coverage: occlusive
Preparation of test site: shaved - Details on analytical verification of doses or concentrations:
- AMOUNT/CONCENTRATION APPLIED:
Amount(s) applied (volume or weight): 2.0 ml
Concentration (if solution): neat - Duration of treatment / exposure:
- On the day prior to application the trunk of each animal was clipped free of hair. For each treated animal, 2 mL/kg of BP83HF was applied to a patch of absorbent paper. The patch was applied to the trunk and held in place beneath a sleeve under a Poroplast bandage. The whole patch assembly was held in place with tape. The patches were left in position for approximately 24 hours. Patches were similarly applied to control animals with the omission of test material. To prevent the animals from gaining access to the sites of application (and hence possibly ingesting traces of test material), collars were applied around the animals heads for a further 24 hours (control and test animals).
- Post exposure period:
- Once per day for 14 days
- No. of animals per sex per dose:
- Control: (5) males; (5) female
2 ml/kg (converted 1.7 g/kg): (5) males; (5) females
- Control animals:
- yes
- Details on study design:
- SCORING SYSTEM: Draize scale
- Dermal response observations: daily
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight
- Details on results:
- Irritant/corrosive response data:
There were no animal deaths prior to study termination. Well-defined erythema was noted upon removal of the test patches in all animals exposed to BP83HF, generally persisting for a further 24 hours. Scab formation was subsequently observed on Day 5 and skin flaking was noted on Day 6 in all treated animals, persisting for a few days only in most animals. Plaster marks were noted on all test and control animals following patch removal; this is an artifact of the test procedure and is commonly seen in studies of this type. No other significant signs of ill health, behavioral change or reaction to treatment were noted.
Other effects:
The body weight gain of male rats was unaffected by treatment with the test material. A marginally larger overall weight gain was recorded for treated female rats when compared with the controls; this was considered to have arisen fortuitously and not related to treatment with BP83HF.
Post mortem examination of all animals killed at termination revealed an area of diffuse subcutaneous haemorrhage beneath the dorsal patch site in one male exposed to BP83HF. However, no other findings considered to be related to treatment were observed and no tissues were processed further for histopathological examination.
Post mortem examination of all animals killed at termination revealed an area of diffuse subcutaneous haemorrhage beneath the dorsal patch site in one male exposed to BP83HF. However, no other findings considered to be related to treatment were observed and no tissues were processed further for histopathological examination. - Relevance of carcinogenic effects / potential:
- INTERPRETATION OF RESULTS: not irritating
CRITERIA USED FOR INTERPRETATION OF RESULTS: EU - Conclusions:
- The average erythema score (24, 48, and 72 hours) was 1.35. Classification as a dermal irritant is not warranted under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP) or under Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations.
- Executive summary:
In this study, 10 rabbits were exposed to 2.0 ml of BP83HF via an occlusive patch. Dermal responses were evaluated once a day for 14 days. Skin irritation was scored according to the Draize method of scoring. At the 24 and 48 hour observations, all animals were noted with a well defined erythema. Only one animal was noted with well defined erythema at the 72 hour observation. After 72 hours, all animals were free of dermal irritation. The average erythema score (24, 48, and 72 hours) was 1.35. This study was conducted to acceptable, well-documented scientific principles. Classification as a dermal irritant is not warranted under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP) or under Directive 67/518/EEC for dangerous substances and Directive 1999/45/EC for preparations.
Referenceopen allclose all
Irritation parameter |
erythema score |
Basis |
mean |
Time point |
24 hours |
Score |
2 |
Max. score |
2 |
Reversibility |
fully reversible after 72 hours |
Remarks |
Irritation parameter |
erythema score |
Basis |
mean |
Time point |
48 hours |
Score |
ca. 2 |
Max. score |
2 |
Reversibility |
fully reversible after 72 hours |
Remarks |
Irritation parameter |
erythema score |
Basis |
mean |
Time point |
72 Hours |
Score |
ca. 0.2 |
Max. score |
2 |
Reversibility |
fully reversible after 72 hours |
Remarks |
Only one female rabbit displayed an erythema score of 2.0 at the 72 hour observation. Reversed in all other 9 animals. |
Irritation parameter |
erythema score |
Basis |
mean |
Time point |
24-72 hours mean |
Score |
ca. 1.35 |
Max. score |
2 |
Reversibility |
fully reversible within: 72 hours |
Remarks |
Irritation parameter |
edema score |
Basis |
mean |
Time point |
24-72 hours |
Score |
ca. 0 |
Max. score |
0 |
Reversibility |
|
Remarks |
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Quality of whole database:
- Supporting read across studies available for assessment.
Justification for classification or non-classification
Hydrocarbons, C12-C16, n-alkanes, isoalkanes, cyclics, aromatics (2-25%) does not meet the criteria for classification as a carcinogen under the Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP).
Additional information
The available read across data and available weight of evidence demonstrate that Hydrocarbons, C12-C16, n-alkanes, isoalkanes, cyclics, aromatics (2-25%) is highly unlikely to be carcinogenic and is not classifiable as a carcinogen. Further testing is not required under Annex XI, section 1.2.
No standard carcinogenicity studies are available for Hydrocarbons, C12-C16, n-alkanes, isoalkanes, cyclics, aromatics (2-25%). However, with regard to the molecular structure of the substance, no carcinogenic potential is expected. Moreover, in investigations on read across mutagenicity (in vitro and in vivo) as well as in read across repeated dose toxicity studies (oral route and via inhalation), neither genotoxicity nor an indication for neoplastic lesions was observed.
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